Child mortality in the United States is most commonly attributed to trauma and sepsis, the major research focus of our research team at the Children's Hospital of Pittsburgh Site of the National Institutes of Child Health and Development (NICHD) Collaborative Pediatric Critical Care Research Network (CPCCRN). This is a renewal application to continue participation in the third cycle of the NICHD-CPCCRN with the goals of collaboratively supporting existing and new studies developed by the Pediatric Trauma and Critical Illness Branch network and also extending our center's novel work within the CPCCRN in host-pathogen interactions in trauma and sepsis. Over the past 9 years our center has provided 24,000 patients to over 22 CPCCRN studies. Our center's program of research in host-pathogen interactions has led to three CPCCRN approved studies. In the first cycle we showed that trauma patients have a two-fold increased risk of developing nosocomial infection and sepsis compared to non-trauma patients. In the second cycle we commenced the ongoing NIGMS-R01 funded Inflammation Phenotypes in Pediatric Severe Sepsis study (PI: Carcillo) which examines the influence of host inflammation phenotype response on nosocomial infection and sepsis outcomes in trauma and non-trauma patients. In our new concept proposal for this third cycle we respond to the NIH roadmap initiative's call for improved understanding of the role of the microbiome in health and disease by evaluating microbiome perturbations in critical illness. In our single center pilot study we found that critically ill children suffered `dysbiosis with loss of microbiome diversity and site specificity with a tendency to formation of an abundant microorganism (> 30% of the microbiome) which could be found in the patient's room and in the patient two days before the onset of nosocomial infection. If we demonstrate that these findings are generalizable across the CPCCRN then this will open the possibility of a new era of microbiome based medicine for prevention and treatment of nosocomial infection and sepsis in critically injured children.